Clinical considerations in the management of non-alcoholic steatohepatitis cirrhosis pre-and post-transplant: A multi-system challenge

Non-alcoholic steatohepatitis(NASH) is the most common chronic liver disease worldwide, and the fastest growing indication for liver transplantation in the United States. NASH is now the leading etiology for liver transplantation in women, the second leading indication for men, and the most common cause amongst recipients aged 65 years and older. Patients with end-stage liver disease related to NASH represent a unique and challenging patient population due the high incidence of associated comorbid diseases, including obesity, type 2 diabetes(T2 D), and hypertension. These challenges manifest in the pre-liver transplantation period with increased waitlist times and waitlist mortality. Furthermore, these patients carry considerable risk of morbidity and mortality both before after liver transplantation, with high rates of T2 D, cardiovascular disease, chronic kidney disease, poor nutrition, and disease recurrence. Successful transplantation for these patients requires identification and management of their comorbidities in the face of liver failure. Multidisciplinary evaluations include a thorough pre-transplant workup with a complete cardiac evaluation, control of diabetes, nutritional support, and even, potentially, consultation with a bariatric surgeon. This article provides a comprehensive review of the conditions and challenges facing patients with NASH cirrhosis undergoing liver transplantation and provides recommendations for evaluation and management to optimize them before liver transplantation to produce successful outcomes.     

A comparison of survival and pathologic features of non-alcoholic steatohepatitis and hepatitis C virus patients with hepatocellular carcinoma

AIM: To compare the clinical outcome and pathologic features of non-alcoholic steatohepatitis (NASH) patients with hepatocellular carcinoma (HCC) and hepatitic C virus (HCV) patients with HCC (another group in which HCC is commonly seen) undergoing liver transplantation.METHODS: Patients transplanted for HCV and NASH at our institution from January 2000 to April 2011 were analyzed. All explanted liver histology and pre-transplant liver biopsies were examined by two specialist liver histopathologists. Patient demographics, disease free survival, explant liver characteristics and HCC features (tumour number, cumulative tumour size, vascular invasion and differentiation) were compared between HCV and NASH liver transplant recipients.RESULTS: A total of 102 patients with NASH and 283 patients with HCV were transplanted. The incidence of HCC in NASH transplant recipients was 16.7% (17/102). The incidence of HCC in HCV transplant recipients was 22.6% (64/283). Patients with NASH-HCC were statistically older than HCV-HCC patients (P < 0.001). A significantly higher proportion of HCV-HCC patients had vascular invasion (23.4% vs 6.4%, P = 0.002) and poorly differentiated HCC (4.7% vs 0%, P < 0.001) compared to the NASH-HCC group. A trend of poorer recurrence free survival at 5 years was seen in HCV-HCC patients compared to NASH-HCC who underwent a Liver transplantation (P = 0.11).CONCLUSION: Patients transplanted for NASH-HCC appear to have less aggressive tumour features compared to those with HCV-HCC, which likely in part accounts for their improved recurrence free survival.     

Incidence of hepatocellular carcinoma in outpatients with cirrhosis in Brazil: A 10-year retrospective cohort study

AIM To determine the incidence of hepatocellular carcinoma(HCC) and the impact of HCC surveillance on early diagnosis and survival of cirrhotic outpatients. METHODS In this retrospective cohort study, cirrhotic outpatients undergoing HCC surveillance between March 2005 and March 2014 were analyzed. Exclusion criteria were HIV coinfection; previous organ transplantation; diagnosis of HCC at first consultation; missing data in the medical chart; and less than 1 year of follow-up. Surveillance was carried out every six months using ultrasound and serum alpha-fetoprotein determination. Ten-year cumulative incidence and survival were estimated through Kaplan-Meier analysis. RESULTS Four hundred and fifty-three patients were enrolled, of which 57.6% were male. Mean age was 55 years. Hepatitis C virus and heavy use of alcohol were the main etiologic agents of cirrhosis. HCC was diagnosed in 75 patients(16.6%), with an estimated cumulative incidence of 2.6% in the 1st year, 15.4% in the 5th year, and 28.8% in the 10 th year. Median survival was estimated at 17.6 mo in HCC patients compared to 234 mo in non-HCC patients(P 0.001). Early-stage HCC was more often detected in patients who underwent surveillance every 6 mo or less(P = 0.05). However, survival was not different between patients with early stage vs non-early stage tumors [HR = 0.54(0.15-1.89), P = 0.33].CONCLUSION HCC is a frequent complication in patients with cirrhosis and adherence to surveillance programs favors early diagnosis.     

Immunoglobulin G in non-alcoholic steatohepatitis predicts clinical outcome: A prospective multi-centre cohort study

BACKGROUNDAutoimmune markers including plasma cells (PC), anti-smooth-muscle antibody (ASMA), anti-nuclear antibody (ANA), and raised immunoglobulin G (IgG) are commonly observed in non-alcoholic steatohepatitis (NASH), however their clinical significance is unknown. AIMTo determine if autoimmune markers in NASH patients are independently associated with poorer clinical outcomes.METHODSConsecutive patients with biopsy proven NASH from Christchurch Hospital, New Zealand and Singapore General Hospital (SGH) were included between 2005 to 2016 in a prospective multi-centre cohort study. Patients with other causes of chronic liver disease were excluded. IgG > 14 g/L or globulin fraction > 50%, ANA ≥ 1:40, SMA ≥ 1:40 were considered positive. Multivariate analysis was performed to assess which markers were independently associated with mortality and hepatic decompensation. RESULTSTotal 261 patients were included of which 201 were from SGH. The median age was 53 and 51.9% were male. Advanced fibrosis was present in 31.4% at diagnosis. PC, ASMA, ANA and raised IgG were observed in 13.1%, 4.9%, 27.8% and 30.1% of patients respectively. After multivariate analysis, elevated IgG [Hazard Ratio (HR) 6.79, 95%CI: 2.93-17.15] and fibrosis stage (HR 1.37, 95%CI: 1.03-1.87) were found to be independently associated with increased risk of liver decompensation. Age (HR 1.06, 95%CI: 1.02-1.10) and elevated IgG (HR 3.79, 95%CI: 1.90-7.68) were independent factors associated with higher mortality risk. CONCLUSIONElevated IgG, rather than ANA, ASMA or plasma cells, is independently associated with increased risk of hepatic decompensation and mortality in NASH. It could hence be important for prognostication.     

Long-term outcomes and prognostic factors of patients with obstructive colorectal cancer: A multicenter retrospective cohort study

AIM: To investigate the long-term oncologic outcomes and prognostic factors in patients with obstructive colorectal cancer(CRC) at multiple Japanese institutions.METHODS: We identified 362 patients diagnosed with obstructive colorectal cancer from January 1, 2002 to December 31, 2012 in Yokohama Clinical Oncology Group's department of gastroenterological surgery. Among them, 234 patients with stage Ⅱ/Ⅲ disease who had undergone surgical resection of their primary lesions were analyzed, retrospectively. We report the long-term outcomes, the risk factors for recurrence, and the prognostic factors.RESULTS: The five-year disease free survival and cancer-specific survival were 50.6% and 80.3%, respectively. A multivariate analysis showed the ASAPS(HR = 2.23, P = 0.026), serum Albumin ≤ 4.0 g/d L(HR = 2.96, P = 0.007), T4 tumor(HR = 2.73, P = 0.002) and R1 resection(HR = 6.56, P = 0.02) to be independent risk factors for recurrence. Furthermore, poorly differentiated cancers(HR = 6.28, P = 0.009), a T4 tumor(HR = 3.46, P = 0.011) and R1 resection(HR = 6.16, P = 0.006) were independent prognostic factors in patients with obstructive CRC.CONCLUSION: The outcomes of patients with obstructive CRC was poor. T4 tumor and R1 resection were found to be independent prognostic factors for both recurrence and survival in patients with obstructive CRC.     

Endovascular treatment for transplant renal artery stenosis: A retrospective cohort study

Transplant renal artery stenosis (TRAS) is the most common (1%–23%) vascular complication following kidney transplantation. The aim of this study was to review our experience with an endovascular approach to treat TRAS.We retrospectively reviewed kidney transplant recipients who underwent percutaneous transluminal angioplasty (PTA) due to TRAS in our institute from January 2009 to December 2015. We analyzed the patient''s baseline characteristics, postoperative renal function, blood pressure evolution, and the number of pre- and post-procedure antihypertensive drugs.A total of 21 patients (15 men, 6 women) were treated with the endovascular technique. The predominant presentation was graft dysfunction (76.2%). Stenosis or hemodynamic kinking was located at the anastomosis in 7 (33.3%) patients, proximal to the anastomosis in 13 (61.9%) patients, and distal the anastomosis in 1 (4.8%) patient. PTA without stent placement was performed in 7 patients (33.3%), and PTA with stent placement was performed in 14 patients (67.7%). Serum creatinine levels demonstrated no difference between the pre-procedure level and that on discharge day (1.61 mg/dl [0.47–3.29 mg/dl] vs 1.46 mg/dl [0.47–3.08 mg/dl]; P = .33). The glomerular filtration rate also showed no difference between the pre-procedure value and that on discharge day (53.6 ml/min [22.4–145.7 ml/min] vs 57.0 ml/min [17.56 –145 ml/min]; P = .084). Systolic blood pressure and diastolic blood pressure (DBP) varied from 137 mm Hg (120–160 mm Hg) and 84 mm Hg (70–100 mm Hg) pre-procedure to 129 mm Hg (90–150 mm Hg) and 79 mm Hg (60–90 mm Hg) at discharge, respectively (P = .124 and P = .07). The number of antihypertensive medications significantly decreased from 1.5 (0–6) pre-procedure to 0.5 (0–2) at discharge (P = .023). In our study, there were no technical failures, procedure-related complications or deaths. During the follow-up period, the free-from-reintervention rate was 100%, and graft failures occurred in 2 patients (9.5%) due to rejection.Endovascular procedures for TRAS show a high technical success rate with a low complication rate and a low reintervention rate. PTA showed a trend toward a positive impact on lowering serum creatinine, systolic blood pressure, and diastolic blood pressure and improving estimated glomerular filtration rate, and the number of antihypertensive medications could be significantly reduced after this procedure.     

Sequential vs simultaneous revascularization in patients undergoing liver transplantation:A meta-analysis

AIM: We undertook this meta-analysis to investigate the relationship between revascularization and outcomes after liver transplantation.METHODS: A literature search was performed using MeSH and key words. The quality of the included studies was assessed using the Jadad Score and the NewcastleOttawa Scale. Heterogeneity was evaluated by the χ 2and I 2 tests. The risk of publication bias was assessed using a funnel plot and Egger's test, and the risk of bias was assessed using a domain-based assessment tool.A sensitivity analysis was conducted by reanalyzing the data using different statistical approaches.RESULTS: Six studies with a total of 467 patients were included. Ischemic-type biliary lesions were significantly reduced in the simultaneous revascularization group compared with the sequential revascularization group(OR = 4.97, 95%CI: 2.45-10.07; P 0.00001),and intensive care unit(ICU) days were decreased(MD = 2.00, 95%CI: 0.55-3.45; P = 0.007) in the simultaneous revascularization group. Although warm ischemia time was prolonged in simultaneous revascularization group(MD =-25.84, 95%CI:-29.28-22.40; P 0.00001), there were no significant differences in other outcomes between sequential and simultaneous revascularization groups. Assessment of the risk of bias showed that the methods of random sequence generation and blinding might have been a source of bias. The sensitivity analysis strengthened the reliability of the results of this meta-analysis.CONCLUSION: The results of this study indicate that simultaneous revascularization in liver transplantation may reduce the incidence of ischemic-type biliary lesions and length of stay of patients in the ICU.     

Clinical features and outcomes of patients with drug-induced autoimmune hepatitis: A retrospective cohort study

BackgroundDrugs and herbal products can induce autoimmune hepatitis. We assessed frequency and clinical outcomes of patients suffering from drug-induced autoimmune hepatitis.MethodsAll patients with drug-induced liver injury admitted between 2000 and 2011 were retrospectively studied. Diagnoses of drug-induced autoimmune hepatitis and idiopathic autoimmune hepatitis were made according to simplified criteria. After discharge, all patients had regular follow-up and were contacted to update outcomes.ResultsAmong 10,270 in-hospital patients, 136 (1.3%) were diagnosed with drug-induced liver injury. Among them, 12 (8.8%) were diagnosed as drug-induced autoimmune hepatitis (41.7% males, age range 17–73); 8 (66.7%) were with jaundice at admission. Liver biopsies showed a pattern compatible with drug-induced autoimmune hepatitis, featured by severe portal inflammation and lymphoplasmacytic infiltrate. Drug-induced autoimmune hepatitis group had a shorter duration of drug intake, and higher values of transaminases and gamma globulins. All patients received immunosuppressive therapy with subsequent clinical remission, and five achieved a steroid-free long-term remission.ConclusionsA diagnosis of drug-induced autoimmune hepatitis was quite rare in our cohort, and clinical pattern was similar to idiopathic autoimmune hepatitis. Severe portal inflammation, prominent portal-plasma cells, rosette formation and severe focal necrosis were significantly more frequent in drug-induced autoimmune hepatitis as compared to drug-induced liver injury.     

Allogeneic hematopoietic transplantation using haploidentical donor vs. unrelated cord blood donor in pediatric patients: a single-center retrospective study

We retrospectively analyzed outcomes in 67 children with acute leukemia who received hematopoietic stem cell transplantation from alternative allogeneic donors: 29 received a haploidentical family donor and 38, an unrelated cord blood donor. All transplantations were performed from 1996 through 2010 in our center. Neutrophil and platelet engraftment were significantly delayed after cord blood transplantation. The median times to neutrophil and platelet recovery were 13 d (7-34) and 11 d (5-70) after haploidentical transplant and 20 d (9-125) and 56 d (12-200) after cord blood (P < 0.001). All supportive care measures included red blood cell, and platelet transfusions were significantly increased in cord blood transplantation group.Transplant-related mortality rates was lower with haplo donors (25 ± 9%) than with cord blood donors (47 ± 9%) (P < 0.05). Acute graft-versus-host disease (GVHD) more than grade II was also lower in haploidentical transplants (19 ± 7%) than in cord blood transplants (44 ± 10%) (P < 0.03). Relapse and chronic GVHD incidence were not significantly different in the two groups. Leukemia-free survival was higher after haploidentical transplants (44 ± 10%) than after cord blood transplants (33 ± 7%) (P < 0.03). Main differences were observed in patients diagnosed with acute lymphoblastic leukemia: haplo, 41 ± 13%; cord blood, 26 ± 9% (P < 0.03) and in advanced phase of disease: haplo, 37 ± 14%; cord blood, 21 ± 8% (P < 0.05). In conclusion, haploidentical transplants are a good and promising alternative option for patients with childhood leukemia who lack an human leukocyte antigen-matched donor (sibling or unrelated donor).     

Clinical characteristics and outcomes of COVID-19 in patients with autoimmune hepatitis: A population-based matched cohort study

BACKGROUND Patients with autoimmune hepatitis(AIH) require life-long immunosuppressive agents that may increase the risk of poor corona virus disease 2019(COVID-19)outcomes.There is a paucity of large data at the population level to assess whether patients with AIH have an increased risk of severe diseases.AIM To evaluate the impact of pre-existing AIH on the clinical outcomes of patients with COVID-19.METHODS We conducted a population-based,multicenter,propensity score-matched cohort study with...     

Hepatocellular injury and the mortality risk among patients with COVID-19: A retrospective cohort study

BACKGROUNDClearly, infection with severe acute respiratory syndrome coronavirus 2 is not limited to the lung but also affects other organs. We need predictive models to determine patients’ prognoses and to improve health care resource allocation during the coronavirus disease 2019 (COVID-19) pandemic. While treating COVID-19, we observed differential outcome prediction weights for markers of hepatocellular injury among hospitalized patients.AIMTo investigate the association between hepatocellular injury and all-cause in-hospital mortality among patients with COVID-19.METHODSThis multicentre study employed a retrospective cohort design. All adult patients admitted to Al-Azhar University Hospital, Assiut, Egypt and Abo Teeg General Hospital, Assiut, Egypt with confirmed COVID-19 from June 1, 2020, to July 30, 2020 were eligible. We categorized our cohort into three groups of (1) patients with COVID-19 presenting normal aminotransferase levels; (2) patients with COVID-19 presenting one-fold higher aminotransferase levels; and (3) patients with COVID-19 presenting two-fold higher aminotransferase levels. We analysed the association between elevated aminotransferase levels and all-cause in-hospital mortality. The survival analysis was performed using the Kaplan–Meier method and tested by log-rank analysis.RESULTSIn total, 376 of 419 patients met the inclusion criteria, while 29 (8%) patients in our cohort died during the hospital stay. The median age was 40 years (range: 28-56 years), and 51% were males (n = 194). At admission, 54% of the study cohort had liver injury. The pattern of liver injury was hepatocellular injury with an aspartate aminotransferase (AST) predominance. Admission AST levels were independently associated with all-cause in-hospital mortality in the logistic regression analysis. A one-fold increase in serum AST levels among patients with COVID-19 led to an eleven-fold increase in in-hospital mortality (P < 0.001). Admission AST levels correlated with C-reactive protein (r = 0.2; P < 0.003) and serum ferritin (r = 0.2; P < 0.0002) levels. Admission alanine aminotransferase levels correlated with serum ferritin levels (r = 0.1; P < 0.04). Serum total bilirubin levels were independently associated with in-hospital mortality in the binary logistic regression analysis after adjusting for age and sex but lost its statistical significance in the fully adjusted model. Serum ferritin levels were significantly associated with in-hospital mortality (P < 0.01). The probability of survival was significantly different between the AST groups and showed the following order: a two-fold increase in AST levels > a one-fold increase in in AST levels > normal AST levels (P < 0.0001).CONCLUSIONLiver injury with an AST-dominant pattern predicts the severity of COVID-19. Elevated serum ferritin levels are associated with fatal outcomes.     

Lifestyle versus ezetimibe plus lifestyle in patients with biopsy-proven non-alcoholic steatohepatitis (LISTEN): A double-blind randomised placebo-controlled trial

Background and aimsThe LISTEN trial (ClinicalTrial.gov accession: NCT01950884) is a phase IV 52 weeks double blind parallel randomized controlled trial that evaluated the effect of ezetimibe plus lifestyle and dietary intervention (eze) vs. lifestyle and dietary intervention alone (placebo) on progression and complications of non-alcoholic steatohepatitis (NASH) evaluated by liver histology.Methods and resultsForty patients with NASH ascertained by histology were randomly allocated on the two study groups and subjected to a follow-up of 52 weeks, when they underwent a second liver biopsy. Main composite end point (EP) was based on the histological improvement in the severity of NASH.Thirty patients completed the study, Eze treatment was not able to improve the primary EP in comparison with placebo, with and odds ratio of 1.029 (0.18–6.38), p = 0.974. Treatment emergent adverse events registered during the study were not more prevalent in the treatment arm.Conclusionsezetimibe administered on top of lifestyle and dietary modification failed to improve the histology of NASH in comparison with lifestyle and dietary modification alone.Trial accession numberClinicalTrial.gov: NCT01950884.     

Progressive liver injury and increased mortality risk in COVID-19 patients: A retrospective cohort study in China

BACKGROUND Liver injury is common and also can be fatal,particularly in severe or critical patients with coronavirus disease 2019(COVID-19).AIM To conduct an in-depth investigation into the risk factors for liver injury and into the effective measures to prevent subsequent mortality risk.METHODS A retrospective cohort study was performed on 440 consecutive patients with relatively severe COVID-19 between January 28 and March 9,2020 at Tongji Hospital,Wuhan,China.Data on clinical features,laboratory parameters,medications,and prognosis were collected.RESULTS COVID-19-associated liver injury more frequently occurred in patients aged≥65 years,female patients,or those with other comorbidities,decreased lymphocyte count,or elevated D-dimer or serum ferritin(P<0.05).The disease severity of COVID-19 was an independent risk factor for liver injury(severe patients:Odds ratio[OR]=2.86,95%confidence interval[CI]:1.78-4.59;critical patients:OR=13.44,95%CI:7.21-25.97).The elevated levels of on-admission aspartate aminotransferase and total bilirubin indicated an increased mortality risk(P<0.001).Using intravenous nutrition or antibiotics increased the risk of COVID-19-associated liver injury.Hepatoprotective drugs tended to be of assistance to treat the liver injury and improve the prognosis of patients with COVID-19-associated liver injury.CONCLUSION More intensive monitoring of aspartate aminotransferase or total bilirubin is recommended for COVID-19 patients,especially patients aged≥65 years,female patients,or those with other comorbidities.Drug hepatotoxicity of antibiotics and intravenous nutrition should be alert for COVID-19 patients.     

Clostridioides difficile infection in liver cirrhosis patients: A population-based study in United States

BACKGROUNDClostridioides (formerly Clostridium) difficile infection (CDI) is an increasingly frequent cause of morbidity and mortality in hospitalized patients. Multiple risk factors are documented in the literature that includes, but are not limited to, antibiotics use, advanced age, and gastric acid suppression. Several epidemiological studies have reported an increased incidence of CDI in advanced liver disease patients. Some have also demonstrated a higher prevalence of nosocomial infections in cirrhotic patients. AIMTo use a large nationwide database, we sought to determine CDI’s risk among liver cirrhosis patients in the United States.METHODSWe queried a commercial database (Explorys Inc^TM, Cleveland, OH, United States), and obtained an aggregate of electronic health record data from 26 major integrated United States healthcare systems comprising 360 hospitals in the United States from 2018 to 2021. Diagnoses were organized into the Systematized Nomenclature of Medicine Clinical Terms (SNOMED–CT) hierarchy. Statistical analysis for the multivariable model was performed using Statistical Package for Social Sciences (SPSS version 25, IBM Corp^TM). For all analyses, a two-sided P value of < 0.05 was considered statistically significant.RESULTSThere were a total of 19387760 patients in the database who were above 20 years of age between the years 2018-2021. Of those, 133400 were diagnosed with liver cirrhosis. The prevalence of CDI amongst the liver cirrhosis population was 134.93 per 100.000 vs 19.06 per 100.000 in non-cirrhotic patients (P < 0.0001). The multivariate analysis model uncovered that cirrhotic patients were more likely to develop CDI (OR: 1.857; 95%CI: 1.665-2.113, P < 0.0001) compared to those without any prior history of liver cirrhosis. CONCLUSIONIn this large database study, we uncovered that cirrhotic patients have a significantly higher CDI prevalence than those without cirrhosis. Liver cirrhosis may be an independent risk factor for CDI. Further prospective studies are needed to clarify this possible risk association that may lead to the implementation of screening methods in this high-risk population.     

Bacterial infection triggers and complicates acute-on-chronic liver failure in patients with hepatitis B virus-decompensated cirrhosis: A retrospective cohort study

BACKGROUND Reports on bacterial infection(BI)in decompensated cirrhosis(DC)is mainly from alcoholic cirrhosis.The role of BI as a trigger or complication of acute-onchronic liver failure(ACLF)in patients with hepatitis B virus decompensated cirrhosis(HBV-DC)remains to be investigated.AIM To investigate the impact of BI on the outcomes of the patients with HBV-DC admitted into the hospital with or without ACLF.METHODS This retrospective study included patients with HBV-DC admitted to two tertiary centers in China.In-hospital overall survival,90-d transplant-free survival,5-year post-discharge survival,and cumulative incidence of ACLF were evaluated.Risk factors for death were analyzed considering liver transplantation as a competing event.RESULTS A total of 1281 hospitalized HBV-DC patients were included;284 had ACLF at admission.The overall prevalence of BI was 28.1%.The patients with BI had a significantly lower in-hospital survival and transplant-free 90-d survival than those without,in both the patients admitted with and without ACLF.The presence of BI significantly increased the risk of developing ACLF[subdistribution hazard ratio(sHR)=2.52,95%CI:1.75-3.61,P<0.001]in the patients without ACLF.In the patients discharged alive,those who had an episode of BI had a significantly lower 5-year transplant-free survival.BI was an independent risk factor for death in the patients admitted without ACLF(sHR=3.28,95%CI:1.93-5.57),while in ACLF admissions,the presence of pneumonia,but not other type of BI,independently increased the risk of death(sHR=1.87,95%CI:1.24-2.82).CONCLUSION BI triggers ACLF in patients with HBV-DC and significantly impairs short-term survival.HBV-DC patients should be monitored carefully for the development of BI,especially pneumonia,to avoid an adverse outcome.